Regulation of resistance to CDK4/6 inhibitor in breast cancer

乳腺癌对 CDK4/6 抑制剂耐药性的调节

• 批准号: 10560131
• 负责人: Shunqiang Li
• 金额: $ 65.05万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-22 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560131
• 关键词: Affect; Aromatase Inhibitors; Breast Cancer Cell; Breast Cancer Patient; CDK4 gene; Cancer Biology; Cell Nucleus; Clinical Oncology; Clinical Research; Combined Modality Therapy; Cyclin-Dependent Kinases; Cytoplasm; Data; Development; Disease; Drug Combinations; Drug Screening; Drug resistance; Estrogen receptor positive; FDA approved; Gene Expression; In Vitro; Investments; Link; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic breast cancer; Modeling; Molecular; Monosaccharides; Neoplasm Metastasis; Nuclear Translocation; O-GlcNAc transferase; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Proliferating; Protein Conformation; Protein Isoforms; Proteins; Regulation; Regulatory Pathway; Resistance; Role; Sampling; Serine; Signal Transduction; Structure; Testing; Therapeutic; Threonine; atovaquone; cancer cell; cancer drug resistance; clinical application; drug discovery; follow-up; glycosylation; improved; in vivo; inhibitor; innovation; malignant breast neoplasm; melanocyte; migration; mouse model; multidisciplinary; novel; novel drug combination; novel strategies; prevent; protein function; resistance mechanism; response; senescence; therapy resistant; tool; transcription factor; treatment strategy; tumor; virtual

Project Summary Cyclin-dependent kinase CDK4/6 inhibitor (CDK4/6i) in combination with aromatase inhibitors is the first-line treatment for ER+ advanced or metastatic breast cancer. Despite CDK4/6 inhibitors significantly improve overall survival of such patients, not all patients respond to these drugs and most patients whose tumors initially respond to CDK4/6i eventually develop acquired resistance. Although many efforts have been invested into the studying mechanism of resistance, CDK4/6i resistance remains a big challenge for HR+ breast cancer. Thus, it is urgent to develop new approaches to overcome resistance in CDK4/6i resistant breast cancer (CRBC). O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is one type of glycosylation that occurs when a monosaccharide, O-GlcNAc, is added onto serine or threonine residues of proteins by O-GlcNAc transferase (OGT). O-GlcNAcylation is involved in a range of cellular activities and aberrant O-GlcNAcylation has been implicated in a host of diseases including cancer. However, the role of O-GlcNAcylation in cancer drug resistance remains largely unknown. Through an innovative quantitative high throughput combination screen (qHTCS) and follow-up extensive preliminary studies using cellular and molecular approaches, we identified a novel OGT-mediated mechanism regulating the resistance to CDK4/6i in ER+ breast cancer. The major objective of this proposal is to determine the role of OGT-mediated pathway in the regulation of CDK4/6i resistance in CRBC cells. Specifically, we will (1) investigate the molecular mechanism of how OGT-mediated pathway regulates CDK4/6i resistance in CRBC cells, (2) evaluate the effects of newly identified drug combinational treatments on palbociclib resistance using resistant PDX and syngeneic models, (3) conduct clinical study to further evaluate the correlation between OGT-mediated pathway and CDK4/6i resistance in tumors from patients. The completion of proposed studies will not only elucidate a novel mechanism regulating CDK4/6i resistance in ER+ breast cancer, but also provide an innovative therapeutic strategy to treat CRBC patients.

项目摘要 细胞周期蛋白依赖性激酶CDK 4/6抑制剂（CDK 4/6 i）联合芳香化酶抑制剂是一线 ER+晚期或转移性乳腺癌的治疗。尽管CDK 4/6抑制剂显著改善 这类患者的总生存期，并非所有患者对这些药物有反应， 最初对CDK 4/6 i应答，最终发展为获得性抗性。尽管已经投入了很多努力 在耐药机制的研究中，CDK 4/6 i耐药仍然是HR+乳腺癌的一大挑战。 因此，迫切需要开发新的方法来克服CDK 4/6 i耐药乳腺癌的耐药性 （CRBC）。0-连接的-N-乙酰葡糖胺化（O-GlcNAc化）是当糖基化反应发生时发生的一种类型的糖基化。 单糖O-GlcNAc通过O-GlcNAc转移酶加到蛋白质的丝氨酸或苏氨酸残基上 （OGT）。O-GlcNAc酰化涉及一系列细胞活性，并且异常的O-GlcNAc酰化已经被发现。 与包括癌症在内的一系列疾病有关。然而，O-GlcNAc酰化在抗癌药物中的作用 抵抗力量在很大程度上仍不为人知。 通过创新的定量高通量组合筛选（qHTCS）和随访 我们利用细胞和分子方法进行了广泛的初步研究，发现了一种新的OGT介导的 调节ER+乳腺癌中CDK 4/6 i抗性的机制。这项建议的主要目的是 确定OGT介导的途径在CRBC细胞中CDK 4/6 i抗性的调节中的作用。 具体而言，我们将（1）研究OGT介导的通路如何调节的分子机制， CRBC细胞中的CDK 4/6 i抗性，（2）评估新鉴定的药物组合治疗对CRBC细胞中的CDK 4/6 i抗性的影响。 使用耐药PDX和同基因模型研究palbociclib耐药性，（3）开展临床研究，以进一步评估 OGT介导的通路与患者肿瘤中CDK 4/6 i抗性之间的相关性。的 完成拟议的研究不仅将阐明一种调节CDK 4/6 i抗性的新机制， ER+乳腺癌，而且还提供了一种治疗CRBC患者的创新治疗策略。